Fetal alcohol effects and fetal alcohol syndrome account for a large percentage of metal retardation and behavioral disorders in the United States and impose a tremendous personal and social burden. Understanding how the immature nervous system responds to ethanol is critical to rational intervention strategies. Electrical activity promotes survival of central nervous system (CNS) neurons in vitro and in vivo and prevents natural cell death (NCD) in neurons from many CNS regions. Ethanol depresses CNS electrical activity through interactions with both N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) postsynaptic receptors. Thus it is possible that ethanol enhances developmental NCD. Recent evidence suggests that ethanol exposure is indeed toxic to immature neurons of the forebrain in vivo. The pattern of cell loss is similar to that produced by a combination of glutamate receptor blockade and GABA receptor potentiation. Our evidence suggests that immature hippocampal neurons in vitro are also susceptible to ethanol- induced cell loss, suggesting that susceptibility is intrinsic to neuronal populations affected and that ethanol itself, rather than associated metabolic or nutritional variables, induces the neuronal loss. Hippocampal neurons in culture also die when chronically exposed to GABAmimetics or NMDA receptor blockade. Cell death elicited by all three treatments is prevented by chronically depolarizing neurons. Thus, we have an in vitro model of ethanol-induced neuronal death that will allow us to explore mechanistic questions. We will examine the ultrastructural and biochemical profile of ethanol-induced hippocampal neuronal death in vitro. We will determine whether the interaction of ethanol with NMDA receptors and/or GABA receptors is sufficient to explain the neuronal loss observed in vitro. We will also address whether permanent or acute decreases in calcium signaling are important in cell loss and will determine the time course over which increases in intracellular calcium provide neuroprotection against ethanol-induced cell loss. The proposed experiments should lead to a better fundamental understanding of the mechanisms by which forebrain neurons are susceptible to ethanol-induced death.